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College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
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June 30, 2009

Devils, Metals, and Details

Posted by Derek

Organic synthesis as we know it can't go on without metal-catalyzed bond-forming reactions. There are too many of them, and they're just too useful. Palladium's the workhorse, followed by copper, then you've got rhodium, nickel, and a host of others (gold's been popular the last few years). We have a. . .fairly good idea of what's going on in these reactions, but not quite good enough. If we really understood all the factors involved, there wouldn't be six garbonzillion different sets of conditions for these things, would there?

A short paper's just come out in Angewandte Chemie that illustrates some of the trickiness involved. Carsten Bolm's group at Aachen has published several interesting iron-catalyzed coupling reactions using good old ferric chloride. These are aryl-amine, aryl-ether, aryl-amide and aryl-sulfide-forming procedures, which cover a lot of ground. (Interestingly, it was one of those sulfide papers that was recently plagiarized by another set of authors). But there were always a few kinks, such as variable yield depending on which bottle of ferric chloride was used.

Well, organometallic chemists are used to that sort of thing. But Bolm has gone back to look at things closely, in collaboration with Stephen Buchwald of MIT (whose group has published many similar couplings with other metal systems), and found a surprise. The iron chloride isn't doing a thing. In fact, as you go to more and more pure sources of the reagent, the yield drops off. But it never goes away, even with the 99.9% pure stuff. That's because it seems to be copper (I) contaminants doing the coupling, even at the parts-per-million level.

There are some startling tables in the paper. For coupling pyrazole onto an aryl iodide, for example, Bolm's group had found in 2007 that they could get 87% yield using >98% ferric chloride from E. Merck, along with dimethylethylene diamine as a cosolvent. If you use the >98% from Aldrich under the same conditions, though, you get 26% yield. And the Aldrich >99.99 stuff gives you only 9%. But if you add five ppm copper (I) oxide to that last reaction, the yield goes up to 78%. And if you leave the ferric chloride out completely, and just go with a trace of copper, the yield is exactly the same (it goes down if you run the same trace-of-copper without the diamine, which seems to be complexing it up into solution).

The other couplings that were reported seem to follow the same pattern. This must really be a disappointment to Bolm and his group, because their work was, among other things, an attempt to get away from copper and palladium. Still, this appears to be a much cleaner and more efficient copper reaction than a lot of the procedures out there.

This sort of thing has happened before in organometallic chemistry. There's a well-known example of nickel contamination in a chromium-mediated reaction from the mid-1980s, and more recently, a report of supposed "metal-free" couplings which appear to have been catalyzed by parts-per-billion levels of palladium found in the sodium carbonate being used as a base, of all things. Tricky things, these metals.

Probably there are quite a bit of undiscovered cases in organometallics, where it's a small contaminant complex that you barely see in the NMR that is doing the catalysis and not the species that is the main one in the NMR.

A good way to make sure is to do some kinetic curves and Hammet plots, but that takes too much time in some cases and it might be asking for too much from a group with limited means. A substitute may be reproducibility. Prepare the organometallic complex a few times and see if yields vary widely from batch to batch. It doesn't guarantee no funny business, but at least it cuts down on a lot of it.

I am churlishly delighted to see this kind of article - it describes what can happen in the methodology project, and it shows that a careful reproducibility/optimization work was done in this case. Its very practical too - process chemists will be delighted to learn that they don't need to load up their reaction with 20mol% of copper iodide.

I think FeCl3 is not such a useless additive in Cu-catalyzed arylation with aryl iodides. Iodide can have inhibitory effect and Fe(III) oxidizes it to I2.

It seems that it would have been more appropriate to release a correction of the former papers by Bolm et al. instead of selling these findings with this correspondence. It looks rather than an advertisement to his communication in Angew. Chem (DOI: 10.1002/anie.200902236) at the same day!

Interesting post but I would disagree that if us organometallic chemists understood exactly how these metal-catalysed reactions worked we would have less diverse sets of reaction conditions. I think the more you know about a reaction the more you can tailor it for your substrate...

Metals contamination can get you! I am quantitating a compound that can easily make Na adducts in the MS, depending on which vial brand you use. Blah. I've just resolved to adding ammonium acetate to the bunch to elimnate that prob. Thank goodness I found a solution to that prob(thanks to my labmates)!

My graduate advisor taught our group that copper chemistry actually originated from European chemists using copper-contaminated bottles of magnesium when making Grignard reagents. With some bottles of magnesium they oberved 1,2-addition to enones, while with other sources of magnesium people observed 1,4-addition.

Interesting that this comes up time and again. I guess the lesson is that we should keep this in mind when we discover new metal-mediated organic reactions...

When you order a chemical, e.g. from SA, you could request a certificate of analysis, where all the impurities are reported, even at ppm level. FeCl3 at 98% has 2% of impurities, 2%!
If you use this material as a catalyst, you shoul d know what is in it, especially if you are going to make a paper whit it!
The big difference between an organometallic chemist and a "catalytic" chemist is that the former makes the catalysts by himself...., the latter just mixes what is commercially available....

Most metal complexes are sold with their purity on a "metal basis", which means that the metal is 98% iron, no guarantee at all on what oxidation or counterion/ligand is contained. All the solid state chemists I know add purification (usually CVD) as their first synthetic step.